BACTERIAL INFECTIONS CAUSED BY: MYCOBACTERIA 

TUBERCULOSIS

A chronic, recurrent infection, most commonly in the lungs.

Once infection is established, clinical tuberculosis (TB) may develop within months or may not occur for years or even decades.

Etiology, Epidemiology and Incidence

TB refers only to disease caused by Mycobacterium tuberculosis, M. bovis, or M. africanum. Other mycobacteria cause diseases similar to TB (see below), but they generally respond poorly to drugs that are effective for TB.

In developed countries, human TB occurs almost exclusively from inhalation of organisms dispersed as droplet nuclei from a person with pulmonary TB whose sputum smear is positive. M. tuberculosis may float in the air for several hours, thus increasing the chance of spread. Spread can occur in mycobacteriology laboratories and autopsy rooms, in part because the hydrophobic nature of the organism facilitates aerosolization. Fomites appear to play no role in their spread.

Case rates vary by country, age, race, sex, and socioeconomic status. In the USA, 21,337 cases were reported in 1996 for an incidence of 8/100,000. Although TB has been almost eliminated in some segments of the population, it is still prevalent in others, such as in persons > 70 yr old, in whom the disease occurs in both sexes and all races with an incidence as high as 200/100,000. TB is twice as prevalent in blacks as in whites in all age groups (see below).

Although specific immunologic defense against TB occurs only after infection, considerable innate defense may occur against its initial invasion. Consequently, many health care personnel can work closely with TB patients for years without a conversion of the tuberculin skin test. Blacks are less resistant to initial invasion than whites, partly accounting for the greater prevalence of infection among blacks. Since incidence always parallels prevalence, blacks also have a higher incidence of TB.

The incidence of TB has increased alarmingly among persons infected with HIV, particularly black and Hispanic IV drug users, most commonly city-dwelling men 25 to 44 yr old. Incidence is lower in white, middle-class homosexual men with AIDS. Active TB is due both to recrudescence of dormant TB infection and to newly acquired infection because HIV infection produces profound immunodeficiency.

Signs of a potentially very dangerous epidemic of TB have already appeared. The advent of HIV infection has created the circumstances not only for an increased incidence of TB (up 30% in New York State in 1992 to 1993) but also for the development of organisms resistant to all first-line drugs. The incidence of TB increased from 1989 to 1992, but since then more strict control measures appear to have been effective. However, the threat of drug-resistant organisms remains.

Pathogenesis

The stages of TB are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB. Ninety to 95% of primary TB infections go unrecognized, producing only a positive tuberculin skin test and a latent or dormant infection. Primary TB may become active at any age, producing clinical TB in any organ, most often the apical area of the lung but also the kidney, long bones, vertebrae, lymph nodes, and other sites. Often, activation occurs within 1 to 2 yr of initial infection, but may be delayed years or decades and activate after onset of diabetes mellitus, during periods of stress, after treatment with corticosteroids or other immunosuppressants, in adolescence, or in later life (> 70 yr of age), but especially after HIV infection. The initial infection leaves nodular scars in the apices of one or both lungs, called Simon foci, which are the most common seeds for later active TB. The frequency of activation seems unaffected by calcified scars of primary infection (Ghon foci) or by residual calcified hilar lymph nodes. Subtotal gastrectomy and silicosis also predispose to development of active TB.

Prophylaxis

Chemoprophylaxis is indicated principally in persons whose tuberculin skin test converted from negative to positive within the previous 2 yr. Thus, treatment is always indicated in small children, in whom infection must be recent, and in older children and adults < 25 yr old, in whom infection is likely to be recent and who are at high risk for developing clinical TB. In the elderly, prophylaxis is indicated only when conversion of the tuberculin skin test is definite (ie, an increase of >= 15 mm from a previously negative reaction; the progression from a single negative test to a positive reaction on a repeat test 1 to 6 wk later should be considered a booster-positive reaction, not a conversion).

Prophylaxis is strongly indicated for any HIV-infected person whose tuberculin reaction is >= 10 mm because the protective effect of T-cell immunity is lost. It is also indicated for reactors (induration of >= 10 mm) who show apical scarring of old TB (Simon foci), have insulin-dependent diabetes mellitus, are receiving or are likely to be receiving prolonged corticosteroid therapy, or have had a gastrectomy, end-stage renal disease, or gastric stapling.

Prophylaxis is strongly indicated in any child < 4 yr old (whether tuberculin-negative or tuberculin-positive) who is a household or close contact with a person whose sputum smear is positive for acid-fast bacilli presumed to be M. tuberculosis. In this age group, the infection may progress so rapidly that serious disease may develop before the test becomes positive.

Chemoprophylaxis generally consists of isoniazid unless resistance is suspected. The dose is 300 mg/day for 6 to 9 mo for adults. For children, the dosage is 10 mg/kg/day, up to 300 mg, given as a single morning dose. In both infected children and elderly tuberculin converters, isoniazid therapy has been shown to be 98.5% effective in preventing development of clinical TB.

The BCG vaccine, made from an attenuated strain of M. bovis, has been used in developing countries with a high prevalence and incidence of TB among young persons. It has little use in the USA, unless the index case cannot be treated satisfactorily. Previous vaccination often causes a positive skin test reaction. Multiple field trials have failed to conclusively demonstrate protective efficacy of BCG against uncomplicated TB, although data suggest some degree of protection against tuberculous meningitis in infants.

It is no longer necessary to hospitalize persons with clinical TB to protect their close contacts. Any risk will already have been realized by the time the diagnosis is made and treatment started. Patients usually become noninfectious within 10 to 14 days of the start of effective therapy. However, good judgment should be used; eg, an infected person should not be permitted to work in a newborn nursery until cultures and/or polymerase chain reaction are consistently negative. Incarceration for supervised therapy is occasionally necessary for recalcitrant patients with infectious TB. Since AIDS patients can spread M. tuberculosis to normal hosts, great care should be taken to identify TB promptly, provide multiple drug therapy, and maintain upper air sterilization with ultraviolet lights in rooms of patients where TB is possible until it is ruled out. M. avium-intracellulare organisms are not transmitted from person to person. Upper air sterilization is also useful in protecting AIDS patients from various airborne infections.

Treatment

Chemotherapy is extremely effective and usually curative if the full course is taken. Antituberculous drugs include five that are bactericidal in the usual doses and three that are bacteriostatic in usual doses. Even strains of tubercle bacilli that are considered susceptible to a drug invariably include a small number (ie, 1/1,000,000) that are resistant. Therefore, disease may improve at first in response to a single drug and then worsen as the resistant mutants multiply unchecked. Resistant mutants to any bactericidal drug occur in susceptible strains at a rate of about 1/1,000,000 replications. Thus, to prevent development of resistance, clinical TB must always be treated with at least two drugs that act through different mechanisms. Other drugs should be added in inner-city patients where spread of isoniazid-resistant TB is common and cannot be cured with the two most effective drugs. 

A single drug is used when clinical disease is absent and the population of organisms is small (ie, < 10,000 to 100,000 compared with 1 × 109 in a cavitary case). Examples include early infection identified by tuberculin conversion but not yet presenting as either an x-ray lesion or clinical illness, or an old lesion that has been healed for years but was never treated sufficiently to kill the residual organisms. The elderly may experience more toxicity from treatment: persons > 60 yr with recrudescent infection and no history of prior effort at therapy usually can be treated satisfactorily with rifampin and isoniazid because they had acquired the infection decades earlier, long before availability of modern drugs.

TB in HIV-infected persons generally responds well to usual regimens when in vitro study shows susceptibility. As they become available, newer drugs should be used for multidrug-resistant strains, but always along with other effective drugs. Therapy should be continued for 6 to 9 mo after conversion of sputum cultures to negative.

In persons with smear-positive pulmonary TB and with extrapulmonary TB, therapy with at least two drugs (isoniazid and rifampin) should be continued for 9 mo. The duration may be shortened if pyrazinamide is given for the first 2 mo and particularly if streptomycin or ethambutol is also given for the first 2 mo. Pulmonary TB therapy may be shortened to 6 mo if three initial sputum smears are negative, indicating that the number of organisms is relatively small. 

When sputum culture has not converted to negative within 5 mo, a single drug, no matter how potent, should not be added in an attempt to effect cure. The treatment failure is probably due to development of resistance to one and possibly both drugs used initially; adding a third drug simply ensures that resistance to it also will soon develop. Rather, two or more drugs to which the organisms are sensitive should be added in fully effective doses, and the total duration of therapy should be extended to at least 6 mo after the sputum culture has completely converted to negative. 

In children, when hilar adenopathy is present, therapy with three drugs is usually advisable, ie, isoniazid, rifampin and pyrazinamide, for 6 mo. When no abnormality can be detected on posterior-anterior and lateral chest x-rays and the child is clinically well, therapy with isoniazid alone (10 to 20 mg/kg in a single daily dose for 6 mo) is adequate unless the source case has drug-resistant TB.

Isoniazid is the drug most likely to lose its efficacy, since its great effectiveness may leave behind resistant mutants to multiply and become the dominant strain. IM streptomycin is usually effective unless the patient had received it previously, in which case capreomycin may be substituted at the same dosage. Oral pyrazinamide is also bactericidal and quite effective. Resistance to ethambutol is uncommon, because it is not sufficiently effective in the dosage commonly used (15 mg/kg/day) and thus does not promote preferential survival of resistant mutants. A dosage of 25 mg/kg/day for the first 2 mo is needed to achieve a bactericidal effect. It should then be reduced to 15 mg/kg to avoid optic neuritis. 

Sputum specimens should be tested weekly at first and then twice monthly during the first 2 mo of therapy to establish a record of response to therapy. Effective therapy quickly reduces the number of organisms in the sputum so that smear and culture results usually convert to negative within 2 mo. When the sputum smear is highly positive at the outset, it may remain positive (partly because of excretion of dead organisms) for 2 to 3 mo after the culture converts to negative. A delay in culture conversion suggests inadequacy of the drug regimen (ie, the organisms are resistant) or of compliance. Strict compliance with the multiple drug regimen is so important that the drugs are usually given under the direct observation of a responsible person. Therapy should be continued at least until six consecutive monthly specimens have been culture-negative. 

Antibiotics: 

Isoniazid (INH) is given orally and is bactericidal, gains ready entrance to body cells and CSF, and is highly effective against large populations of extracellular bacilli. It is the single most useful and least expensive drug for TB. When INH is given in combination with rifampin (RMP), a susceptible organism has about one chance in 1 × 1012 of surviving and replicating.

INH is safe to use during pregnancy. Allergic reactions to INH include rash, drug fever, and, rarely, anemia and agranulocytosis. Serious (but reversible) injury to the liver may occur in 1 to 2% of treated persons < 65 yr old. The risk may reach 4 to 5% in persons > 65 yr old and is also increased in alcoholics. Possible effects that should be reported include anorexia, nausea, vomiting, and jaundice, indicating hepatic toxicity and the need for liver function testing. If the patient reports vomiting, INH should be stopped promptly until results of liver function tests are available. If the transaminase value is very high (>= 500 U/L), INH should not be restarted. With milder elevations and after symptomatic recovery, the patient can safely be challenged with a half dose for 2 to 3 days; if this is tolerated, the full dose may be restarted with close monitoring for symptoms. About 1/2 of the patients who had toxic reactions can tolerate the drug if it is reintroduced in this way. If the patient is receiving both INH and RMP, the rechallenge should be performed with each drug separately. This allows identification of the offending drug that must be withdrawn so that another drug can be substituted. Routine monthly liver function testing is not recommended because harmless transient elevations of serum transaminase levels occur frequently, leading only to confusion. 

Peripheral neuropathy due to INH-induced pyridoxine (vitamin B6) deficiency is most likely to occur in pregnant or poorly nourished persons, alcoholics, cancer and uremic patients, and the elderly. A daily dose of 25 to 50 mg of pyridoxine can prevent this complication, although it may not be needed in children and healthy young adults.

INH delays excretion of phenytoin and its dosage must be decreased.

Rifampin (RMP), given orally, is bactericidal, well absorbed, penetrates well into cells and CSF, and acts rapidly against the large extracellular population of tubercle bacilli. It is also valuable in eliminating largely dormant organisms in macrophages or caseous lesions that can cause late relapse. Thus, RMP should be used throughout the course of therapy. Dosage for adults is 600 mg in a single daily dose; for children, 10 to 20 mg/kg in a single daily dose (maximum dose, 600 mg). Toxic effects include cholestatic jaundice (rare), fever, thrombocytopenia, and renal failure. RMP adds only slightly to the hepatotoxicity of INH. With the 600-mg twice-weekly dosage, allergic flu-like reactions are uncommon. RMP is safe to use during pregnancy. RMP accelerates metabolism of anticoagulants, oral contraceptives, corticosteroids, digitoxin, oral hypoglycemic agents, and methadone. It also tends to reduce vitamin D concentration, which may be dangerous in febrile and seriously ill patients, especially blacks, who generally have a lower vitamin D level than whites. (Vitamin D is essential to the function of macrophages, which protect against M. tuberculosis.) Vitamin D supplementation is advisable in elderly blacks with TB who have been indoors during a prolonged illness or who have spent little or no time in sunlight. Rifapentine, a second generation of rifampin, has a much longer half-life than rifampin and can be given weekly. 

Streptomycin (SM) is very effective, and resistance is still uncommon. SM is given by injection 5 days/wk in a dosage of about 15 mg/kg (usually 1 g for adults, reduced to 0.5 g for those > 60 yr old, < 45 kg [< 100 lb], or who have any degree of renal insufficiency). Pediatric doses must be adjusted for body weight. In patients > 60 yr with renal compromise, the dosage should be reduced to 0.25 g. CSF penetration is poor, and intrathecal administration should not be used if other effective drugs are available.

Possible toxic effects include renal tubular damage, vestibular damage, and ototoxicity. Since these are dose-related, the dosage should not be > 1 g/day, and the drug should not be given daily (rather, 5 days/wk) for > 2 mo. Then it may be given twice a week for another 2 mo if necessary. Patients should be monitored with appropriate testing of balance, hearing, and serum creatinine levels. Allergic reactions include skin rash, drug fever, agranulocytosis, and serum sickness. Flushing and tingling around the mouth commonly accompany each injection but subside quickly. SM is contraindicated in pregnancy because it may damage the 8th cranial nerve in the fetus. 

Pyrazinamide (PZA), a useful bactericidal oral drug, was formerly used only for re-treatment and resistant cases but is now used routinely with INH and RMP or with ethambutol or SM to guard against treatment failure due to INH resistance and to shorten the course of therapy to 6 mo. It is not advisable for routine use in patients > 60 yr old who have never been treated before. Its major toxic effect is hyperuricemia, which is generally mild and only rarely induces gout. The usual dosage of 25 to 30 mg/kg given in a single daily dose avoids the hepatotoxicity that occurred in the past with larger divided doses. Pediatric doses must be adjusted for body weight. 

Ethambutol (EMB) is an oral bacteriostatic drug that deters resistance to bactericidal drugs used in TB therapy. A single dose of 25 mg/kg/day should be used for the first 2 mo of therapy, followed by a less toxic dosage of 15 mg/kg/day once the size of the bacterial population has been greatly reduced. Alternatively, 50 mg/kg may be given twice weekly to achieve a bactericidal blood level with each dose. Toxicity may affect the optic nerve, producing inability to distinguish blue from green; impairment of visual acuity follows. Since both are reversible if detected early, the patient should be instructed to monitor vision by looking at the same blue object and reading a newspaper every day using his usual glasses. A change in either should be reported so that the eyes may be examined and another drug substituted for EMB if optic neuritis is found. Toxicity is rare in doses of the continuation phase of 15 mg/kg/day. EMB is generally avoided in young children who cannot read eye charts and is used in regular dosage in those able to read eye charts. In patients with renal insufficiency, the dosage of EMB should be reduced to 8 to 10 mg/kg/day. It can also be used safely in pregnancy. For patients receiving renal dialysis, the dose should be given after each dialysis session.

Capreomycin is an excellent parenteral bactericidal drug with dosage, effectiveness, and side effects essentially identical to those of streptomycin. Ethionamide and cycloserine are effective, although seldom used because of undesirable side effects (nausea and depression and psychosis, respectively). Levafloxacin, ciprofloxacin, and amikacin appear effective, although they are not approved for TB. Nevertheless, they can be valuable in TB when the organism shows resistance to several drugs. 

Treatment regimens: Initially, RMP and INH may be given daily for 9 mo, or given daily for 1 mo and then twice weekly for 8 mo (the Arkansas regimen). The twice-weekly dose of RMP is 600 mg (as is the daily dose) and of INH, 900 mg. This regimen is most easily achieved with combination capsules (Rifamate) that contain 1/2 the dose of both RMP and INH (300 mg and 150 mg, respectively); two capsules are given daily for 1 mo, then two capsules plus two 300-mg tablets of INH are given twice weekly for the remainder of the course of therapy. This eliminates the potential confusion of reversing the two: three RMP capsules and two INH tablets. More importantly, it eliminates the development of drug resistance as a result of taking either drug alone. 

An alternative regimen consists of RMP, INH, EMB, and PZA given daily for 2 wk under direct supervision, then RMP 10 mg/kg, INH 15 mg/kg, EMB 50 mg/kg, and PZA 50 mg/kg given twice weekly under supervision (the Denver regimen). This regimen can be completed in 6 mo with very little chance of failure or relapse. The large dosages given twice weekly make even EMB bactericidal. This regimen is useful for patients who are unlikely to comply with the treatment regimen without supervision. 

The American Thoracic Society and the Centers for Disease Control and Prevention recommend a regimen of RMP and INH daily for 6 mo, with PZA 30 mg/kg/day for the first 2 mo. The more intensive regimens are preferred in areas where the incidence of INH resistance is high. Generally, since TB in the elderly is caused by organisms sensitive to RMP and INH, these two drugs suffice and are well tolerated. Also, toxic effects are less common and easier to reverse with two drugs than with three.

Other modes of therapy: Surgical resection of a persistent TB cavity may occasionally need to be performed, but only by an experienced surgeon, to eliminate the large population of bacteria that have begun to show drug resistance. 

Corticosteroid therapy is seldom indicated. However, in patients with adult respiratory distress syndrome, excessive fever, or difficulty in breathing, corticosteroids for 2 to 3 wk may be lifesaving. Such therapy is also indicated when cerebral edema accompanies tuberculous meningitis, although it has not been shown to be beneficial in tuberculous pleurisy or pericarditis. Physiologic doses of a mineralocorticoid are adequate in treating the adrenal insufficiency that accompanies Addison's disease. Corticosteroids that are needed for other indications pose no danger in a patient with active TB who is receiving an effective TB regimen. 

Pulmonary Tuberculosis 

Typically, recrudescent disease occurs in nodular scars in the apex of one or both lungs (Simon foci) and may spread through the bronchi to other portions. Recrudescence may occur while a primary focus of TB is still healing but is more often delayed until some other disease facilitates reactivation of the infection. In an immunocompetent person whose tuberculin test is positive (>= 10 mm), exposure to TB rarely results in a new infection, because T-lymphocyte immunity controls small, exogenous inocula promptly and completely. 

In the immunocompetent patient, even large cavities usually heal with appropriate chemotherapy, although drug therapy must be intensive and prolonged. The disease is much more aggressive in immunocompromised persons and, if not properly and aggressively treated, may be fatal in as little as 2 mo from its first symptom.

Symptoms and Signs 

Pulmonary TB is often so nearly asymptomatic that the patient may deny all symptoms except "not feeling well," even though a chest x-ray shows a distinct abnormality. 

Cough is the most common symptom, but may be discounted and ascribed to smoking, a recent cold, or a recent bout of influenza. At first, it is minimally productive of yellow or green mucus, usually on rising in the morning, but becomes more productive as the disease progresses. Dyspnea may result from rupture of the lung (spontaneous pneumothorax) or from a pleural effusion caused by a vigorous inflammatory reaction to a small amount of caseous material extruded from a small, superficial caseous nidus. Although the latter may occur at any stage of the disease, it is most common in a recent infection (progressive primary TB) in young adults. Hemoptysis usually does not occur until the later stage of TB. 

Hilar lymphadenopathy is the most common finding in children, due to lymphatic drainage from a small lesion, usually located in the best ventilated portions of the lung (lower and middle lobes), where most of the inhaled organisms are carried. TB in children usually causes few symptoms, except for a brassy cough, but may be associated with segmental atelectasis. Further swelling of the nodes is common, even after chemotherapy is started, and may produce lobar atelectasis, which usually clears uneventfully as treatment takes effect. Untreated infection may progress to miliary TB or tuberculous meningitis and, if long neglected, rarely may lead to pulmonary cavitation.

The course of TB varies greatly, depending on many factors, such as size of inoculum (number of inhaled infectious organisms), virulence of the organism, competence of host defense, and presence of other diseases (eg, diabetes, HIV infection) or immunosuppressive therapy. The course generally is more rapid among blacks and American Indians than among whites. Whites more commonly have chronic fibrotic disease without obvious symptoms of a serious illness and therefore may remain undiagnosed for months until all other possibilities have been eliminated. Thus, blacks and American Indians are more infectious but for a shorter time before the diagnosis is made and treatment started. Whites may remain infectious for many months before being diagnosed. Culture or biopsy is often required to establish the diagnosis in whites, while acid-fast bacilli (AFB) are more commonly found in the sputum of blacks and American Indians. 

TB in the elderly presents special problems. Long-dormant infection may reactivate, most commonly in the lung but sometimes in the brain or a kidney, long bone, vertebra, lymph node, or anywhere that bacilli were seeded during the primary infection earlier in life. This is often chronic, producing little change in the clinical situation. Such recrudescence can be overlooked for weeks or months, and appropriate studies may be delayed. TB may develop when infection in an old calcific lymph node reactivates and leaks caseous material into a lobar or segmental bronchus, causing a pneumonia that persists despite broad-spectrum antibiotic therapy. When pulmonary TB occurs in a nursing home resident, infection may spread widely. Thus, in nursing home residents, one may see a mixture of typical adult-type TB in the apices of the lungs of long-standing reactors, as well as pleural effusion and pneumonic infiltrates in the middle and lower portions of the lung due to progressive primary TB in previously tuberculin-negative residents. In the USA, miliary TB and tuberculous meningitis, commonly thought of as afflicting young children, are more common in the elderly today.

With HIV infection, progression to clinical TB is much more common and rapid. Instead of a 5 to 10% attack rate in 1 to 2 yr, the attack rate is 50% within 60 days. If the infecting strain is resistant to available drugs, the result is a 50% death rate within a median time of 60 days. 

HIV also reduces both inflammatory reaction and cavitation of pulmonary lesions. As a result, a patient's chest x-ray may be normal, even though AFB are present in sufficient numbers to show on a sputum smear. Recrudescent TB is almost always indicated when such an infection develops while the CD4+ T-lymphocyte count is >= 200/µL. By contrast, the diagnosis is usually infection by M. avium-intracellulare if the CD4+ count is < 50. The latter is noninfectious for others. 

Pleural TB develops when a small subpleural pulmonary lesion ruptures, extruding caseous material into the pleural space. The most common type, serous exudate, results from rupture of a pimple-sized lesion of primary TB and contains very few organisms. Generally, no air leakage occurs, and the effusion may clear spontaneously in a few weeks. However, it may progress to pulmonary TB and even seed other organs. Such a lymphocytic pleural exudate in a young person, even with a negative tuberculin skin test, is so likely to be tuberculous that TB therapy is strongly indicated even though the diagnosis of TB is not proven. A full course of chemotherapy is needed to stop the infection at this early stage. 

Tuberculous empyema with or without bronchopleural fistula is caused by a more massive contamination of the pleural space resulting from rupture of a large tuberculous lesion. Such a rupture allows air to escape and collapse the lung. Either type requires prompt drainage of pus and initiation of multiple drug therapy (see Treatment above).

Diagnosis 

TB is often first suspected from chest x-rays taken either for evaluation of nonspecific symptoms or as part of a workup of an unexplained illness or FUO. In adults, a multinodular infiltrate above or behind the clavicle (most characteristic location) suggests recrudescence of old TB infection. In recent infections (more common in young people), infiltration is more common in the better ventilated middle and lower lung and may be accompanied by an exudative pleural effusion. 

The finding of AFB in a sputum smear is strong presumptive evidence of TB, but a definitive diagnosis is made only on results of polymerase chain reaction (PCR) identification of M. tuberculosis or a sputum culture, which may not be available for 3 wk or more. Examination by PCR takes much less time. Fiberoptic bronchoscopy is helpful in patients who cannot produce sputum; bronchial washings should be submitted for smear and culture. Postbronchoscopy sputum is particularly likely to reveal positive results. Transbronchial biopsy should be performed on infiltrative lesions and the specimen submitted for culture, histologic evaluation, and PCR. Gastric washings have been largely replaced by bronchial washings and biopsy and especially postbronchoscopy sputum. 

When pleural TB is suspected, thoracentesis and pleural biopsy should be performed, with determination of the total protein and glucose content, WBC count and differential, and fluid pH, as well as histologic evaluation and culture. The diagnosis is often missed because of negative culture and skin test results. However, because the chance of active TB developing later is at least 50%, treatment for TB is mandatory. Every case must be reported to the state and local health departments so that close contacts can be tested in search of the source for such a new infection.

The tuberculin skin test, although far from definitive, is an essential adjunct in diagnosis. The standard dose of 5 tuberculin U of purified protein derivative of tuberculin (PPD) in 0.1 mL of solution is injected intradermally, usually on the volar surface of the forearm. An induration of >= 10 mm indicates infection with M. tuberculosis but does not indicate activity of the infection. TB patients who are quite ill may show no reaction to the skin test because of inhibiting antibodies or because so many T cells have been mobilized to the lesion that too few remain to produce a significant skin reaction. The test also may be negative in persons with HIV infection, particularly if the CD4+ cell count is < 200/µL or manifestations of AIDS are present. Multiple-puncture devices are no longer recommended for general use. 

All persons likely to be exposed to TB (eg, living or working in a nursing home or hospital, homeless shelter, or prison) should be tested initially with the 2-step Mantoux test. From 3 to 10% of persons who have no reaction to the first test will develop a significant reaction when the test is repeated 1 to 3 wk later (far too soon to have converted from a new infection). This is called a booster-positive reaction and has about the same significance as a test that is positive the first time. Not using the 2-step test can result in mistaking a booster-positive reaction found a year later for a conversion and in unnecessary prophylactic chemotherapy. 

Baseline skin test results are helpful when previously nonreactive nursing home residents are exposed to a case of infectious TB. An increase of >= 15 mm over the size of the induration in the last negative test is evidence of a new infection. If no clinical or x-ray evidence of active disease is present, the resident should be treated preventively (see under Prophylaxis and Treatment, above).

Extrapulmonary Tuberculosis 

Remote tuberculous lesions can be considered as metastases from the primary site in the lung, comparable to metastases from a primary neoplasm. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints were once commonly caused by ingestion of milk infected with M. bovis. Such infection has been largely eradicated in developed countries by slaughtering cows with a positive TB skin test and pasteurizing all milk and milk products sold in the USA. Today, organs other than the lung may be seeded during a period of silent bacillemia of a recent TB infection. Whether the organism becomes established at a remote site depends on many factors; a few organisms are successful, most are not. Of those that are, many cannot initiate a progressive lesion and become dormant. Thus, the "seed" is planted and may produce an active lesion only later, when other diseases occur or defenses become compromised (as by HIV or old age). HIV infection greatly increases the chance that bacillemia will accompany what otherwise would be simply self-limited primary TB. As a result, a larger proportion of tuberculous lesions in HIV-infected persons are extrapulmonary. 

TB can involve any organ. Rarely, TB of the skin may develop on abraded skin in a patient with cavitary pulmonary TB. TB may infect the wall of a blood vessel and has even ruptured the aorta. TB of the kidney may spread to the epididymis or prostate gland. Adrenal involvement, leading to Addison's disease, formerly was common but now is rare. Trauma to a tendon sheath may cause tuberculous tenosynovitis in a patient with tuberculous involvement of any organ. 

Recrudescence of old infection at any site is common in insulin-dependent diabetics, patients treated with corticosteroids or for malignancy, and in immunosuppressed persons, especially those with HIV infection.

GENITOURINARY TUBERCULOSIS 

The kidney is one of the most common sites for extrapulmonary (metastatic) TB. Often after decades of dormancy, a small cortical focus may enlarge and destroy a large part of the renal parenchyma. The renal pelvis may develop chronic, "sterile" (routine culture-negative) pyelonephritis. Infection commonly spreads to the bladder and, in men, to the prostate, seminal vesicles, and epididymis, causing an enlarging scrotal mass. Infection may spread to the perinephric space, causing caudad dissection of the infection down the psoas muscle and presenting as an abscess on the anterior thigh. Diagnosis can usually be made from a urine culture, especially if the specimen is taken after prostatic massage. Renal cavitation and deformity of the renal architecture are typical manifestations on pyelography. PCR technology helps identify the small number of organisms in such lesions. 

Salpingo-oophoritis can be a complication of primary TB after onset of menarche, when the fallopian tubes become vascular. It may develop early or after considerable latency, presenting as a chronic pelvic inflammatory process or as sterility or ectopic pregnancy due to tubal scarring. Diagnosis in women cannot be made from urine culture. Generally, a laparotomy is required, but occasionally the diagnosis is made from uterine scrapings or laparoscopy. 

TUBERCULOUS MENINGITIS 

Spread of TB to the subarachnoid space may occur as part of generalized dissemination through the bloodstream or from a superficial tubercle in the brain, comparable to pleural contamination from a pulmonary lesion. Meningitis usually occurs without spread of TB elsewhere in the body. In the USA today, meningitis is most common in the elderly, occurring as a manifestation of recrudescence of an infection acquired many years earlier. In areas where TB is common among children, tuberculous meningitis usually occurs between birth and 5 yr following exposure to an infectious parent, babysitter, grandparent, and so forth.

Symptoms are fever (temperature rising to 38.3° C [101° F]), unremitting headache, nausea, and drowsiness, which may progress to stupor and coma. Stiff neck (Brudzinski's sign) and straight leg raising are inconstant but are helpful signs, if present. Stages of tuberculous meningitis are (1) clear sensorium with abnormal CSF, (2) drowsiness or stupor with focal neurologic signs, and (3) coma. Likelihood that CNS defects will become permanent increases with the stage. Symptoms may progress suddenly if the lesion causes thrombosis of a major cerebral vessel. 

Diagnosis is made by examining CSF. However, organisms are generally too sparse to be seen on a stained smear and often are not found even on culture of the fluid. The most helpful CSF findings include a glucose level < 1/2 that in the serum and an elevated protein level along with a pleocytosis, largely of lymphocytes. Examination of CSF by PCR is most helpful, rapid, and highly specific. 

Occasionally, tubercle bacilli established within the brain manifest as a mass lesion or abscess. In the healing or healed state, they produce a mass known as a tuberculoma. Treatment must be given as soon as possible on suspicion of the diagnosis to prevent serious and permanent brain damage. Neurosurgical consultation is needed to determine whether the lesion should be removed under protection of chemotherapy. Such lesions are more common and more aggressive in HIV-infected persons.

MILIARY TUBERCULOSIS (Generalized Hematogenous or Lymphohematogenous Tuberculosis)

When a tuberculous lesion leaks into a blood vessel, massive dissemination of organisms may occur, causing millions of 1- to 3-mm metastatic lesions. Such spread, named miliary because the lesions resemble millet seeds, is most common in children < 4 yr and in the elderly. Bone marrow involvement may produce any of several patterns in peripheral blood: refractory anemia, thrombocytopenia, leukemoid reaction, and others. The seriousness depends on the magnitude of the inoculum. In massive dissemination, the chest x-ray shows thousands of 2- to 3-mm interstitial nodules evenly distributed through both lungs, making diagnosis easy.  

Symptoms include fever (frequently with history of a chill), weakness, malaise, and often progressive dyspnea. However, disseminated TB may occur without a miliary pattern in the chest x-ray, making diagnosis difficult. When disseminated TB is suspected in such a case, chest x-ray should be repeated in a few days, because the millet-sized tubercles may have appeared by then. 

Intermittent dissemination of tubercle bacilli may lead to a confusing chronic illness, presenting as a prolonged FUO. Hematogenous TB in persons with HIV infection produces a serious, often baffling illness with symptoms of both infections. Bone marrow or liver biopsy may show poorly formed granulomas with abundant tubercle bacilli that are later confirmed by culture or PCR. The blood culture may even be positive for tubercle bacilli. Vigorous antituberculous chemotherapy generally improves the symptoms rapidly. M. avium-intracellulare infection (MAIC) often produces bacteremia in AIDS patients and is a preterminal event unresponsive to currently available chemotherapy.

Diagnosis may be made by bronchial washings or protected brush scrapings or by transbronchial biopsy. If this fails, biopsies of the bone marrow and then the liver should follow. Although the tuberculin skin test is usually positive, it may be suppressed, particularly in the febrile and elderly. Diagnosis should be confirmed by PCR, but the finding of granuloma is sufficient to begin chemotherapy while awaiting results. The differential diagnosis includes disseminated fungal infection or lymphangitic spread of carcinoma, both of which can easily be distinguished in biopsy specimens with appropriate staining. 

TUBERCULOUS PERITONITIS 

TB may spread to the peritoneum from involved abdominal lymph nodes or from a tuberculous salpingo-oophoritis. Peritoneal involvement is particularly common in alcoholics with cirrhosis. Symptoms may be mild with fatigue, abdominal pain, and tenderness, or severe enough to mimic acute bacterial peritonitis. The "doughy abdomen" referred to in old textbooks is rarely recognizable. The most reliable diagnostic procedure is a paracentesis and peritoneal needle biopsy. Examination of fluid or peritoneal biopsy for TB histology and PCR identification of M. tuberculosis are most helpful. Finding granulomas in the biopsy along with a positive skin test makes the diagnosis almost as well as finding M. tuberculosis in culture. However, the tuberculin test may be negative if considerable fluid is present. 

TUBERCULOUS PERICARDITIS 

Occasionally, infection spreads to the pericardial sac from recrudescence of dormant infection in a mediastinal lymph node or from tuberculous pleuritis. Signs of heart failure or neck vein distention accompanied by fever and distant heart sounds may be seen, as may pericardial tamponade. Pericardial friction rub and paradoxical pulse may be present. An enlarged cardiac shadow with a water bottle shape may be seen on chest x-ray. Diagnosis usually requires sampling of pericardial fluid or surgical biopsy of the pericardium. The most common differential diagnoses are viral pericarditis and lung carcinoma involvement.

If the tuberculin skin test is positive and clinical signs are consistent with tuberculous pericarditis, antituberculous therapy (see above) should be instituted even before the diagnosis is confirmed. If considerable fluid is present, pressure may be relieved by needle drainage, although surgical intervention to make a pericardial window is preferable for drainage and a diagnostic biopsy.

Prompt institution of two to four antituberculous drugs is the most important treatment. The value of corticosteroid therapy has not been established and is risky unless adequate chemotherapy is being given. 

TUBERCULOUS LYMPHADENITIS

In primary infection with M. tuberculosis, the infection spreads from the infected site in the lung to the hilar nodes. If the inoculum is not too large, other nodes generally are not involved. However, if the infection is not controlled, other nodes in the superior mediastinum may become involved. If organisms reach the thoracic duct, general dissemination may occur. From the supraclavicular area, nodes in the anterior cervical chain may be inoculated, thus sowing the seeds for tuberculous lymphadenitis at a later time. Most infected nodes heal, but the organisms may lie dormant and viable for years or decades and can again multiply and produce active disease. 

The clinical presentation of lymphadenitis includes a mildly tender, slowly progressive swelling of the involved nodes, usually matted into an irregular mass. If treated early and vigorously, they generally subside, but recurrence is common unless therapy is continued for 9 to 12 mo. If untreated, infection may eventually penetrate the skin. Cervical nodes in a tuberculin reactor should not be incised and drained, since this usually produces a chronic, draining, active lesion that is difficult to cure. Surgery, if needed, should be a clean resection of the involved nodes under adequate chemotherapeutic coverage and without wound contamination. 

Late reactivation of long-dormant TB in a hilar or mediastinal node may set off hematogenous spread of infection, tuberculous lobar pneumonia, pericarditis, or even vertebral TB (Pott's disease).

TUBERCULOSIS OF BONES AND JOINTS - Pott's disease

When primary TB occurs in children while the epiphyses are open and the blood supply to bone ends is rich, bacilli often disseminate to the vertebrae and ends of the long bones. Disease may develop quickly or months, years, or decades later. Infection may spread into the articular capsule, causing a monarticular arthritis. Weight-bearing joints are commonly involved, but bones of the wrist, hand, and elbow also may be involved, especially after injury. 

Pott's disease begins in the vertebral body next to the disk space. Characteristically, two vertebrae are involved and the disk space between them is narrowed by caseation. (This differs from metastatic carcinoma, which involves the vertebrae without narrowing the disk space.) If the disease is not diagnosed and treated promptly, the vertebrae may collapse, resulting in paraplegia. Infection is best detected early by MRI, since deformity may not be detectable on spinal x-rays taken early in the illness. If diagnosis cannot be made and symptoms of localized back pain persist or worsen, studies should be repeated. A paravertebral swelling at the involved site may represent an abscess, which, if neglected, may dissect down the psoas muscle and point on the anterior aspect of the thigh. 

Diagnosis may be suspected from symptoms, but CT or MRI is essential. Diagnosis is best confirmed by biopsy; in the spine, bone may be sampled by needle biopsy. At other sites, a biopsy of synovial tissue or bone is necessary. The tissue specimen should be examined histologically and stained for M. tuberculosis, fungi, and other pathogens. It should also be studied by PCR and cultured for TB and other pathogens (eg, Staphylococcus, Brucella, Salmonella, Francisella tularensis). 

Chemotherapy usually suffices if vertebral destruction is limited and the cord is not pinched. If the swelling beside the vertebrae subsides with therapy, it probably is not an abscess and will not need debridement. However, the involved area should be immobilized with a well-fitted brace during chemotherapy. If the swelling does not subside or pain persists, surgical debridement may be necessary. Only the most advanced cases require fixation of the vertebral column by anterior or posterior bone graft.

GASTROINTESTINAL TUBERCULOSIS 

The mucosa of the entire GI tract is resistant to the invasion of tubercle bacilli. Invasion occurs only with prolonged exposure and when the inoculum is enormous, as in cavitary pulmonary TB. In countries where bovine TB is common, ulcers of the mouth and oropharynx may develop from eating contaminated dairy products, and primary lesions may occur in the small intestine. Significant intestinal involvement rarely occurs in developed countries but is still a problem in developing countries. Intestinal invasion generally produces a hyperplastic lesion (inflammatory bowel syndrome) that is usually diagnosed when the patient undergoes laparotomy for suspected carcinoma. Simple resection followed by chemotherapy generally produces excellent results. 

TUBERCULOSIS OF THE LIVER 

Tubercles may be present in the liver of patients with advanced pulmonary TB, miliary TB, or disseminated spread. However, the liver generally heals without incident when the principal site of infection is treated. Patients seriously ill and febrile with pulmonary TB may have abnormal liver function tests. With these patients, the several drugs used should include only one potentially hepatotoxic drug rather than a combination of rifampin and isoniazid. Usually, therapy should be initiated with streptomycin, isoniazid, and ethambutol, so that if liver function worsens, the physician will know it is due to isoniazid, which should be stopped, and rifampin substituted. After the patient improves clinically, therapy can be continued with the more effective and generally less toxic regimen of rifampin and isoniazid. Liver function returns to normal fairly quickly with chemotherapy. 

Tuberculous involvement of the liver occasionally spreads to the gallbladder, leading to obstructive jaundice, which can be diagnosed by laparoscopy.

OTHER MYCOBACTERIAL INFECTIONS RESEMBLING TUBERCULOSIS 

Mycobacteria other than the tubercle bacillus can cause infections in humans. These organisms are commonly found in the environment (soil and water), and exposure is much more frequent than development of disease. Since all of the organisms are less virulent than M. tuberculosis, a defect in local or systemic host defense is usually a precondition for disease. M. avium complex (MAC)--the closely related species of M. avium and M. intracellulare--accounts for most of these diseases. Other noteworthy species are M. kansasii, M. xenopi, M. marinum, M. ulcerans, and the M. fortuitum complex (M. fortuitum and M. chelonei). 

The lungs are the most common site, with occasional cases involving lymph nodes, bones and joints, the skin, and wounds. However, disseminated MAC disease is emerging in importance in patients with AIDS, and resistance to antituberculous drugs is the rule (except in M. kansasii and M. xenopi). Person-to-person transmission is rare but can occur in compromised hosts. 

Pulmonary Disease 

Most pulmonary infections involve MAC, but a few are due to M. kansasii, M. xenopi, and M. fortuitum complex. The typical patient is a middle-aged white man with prior lung problems such as chronic bronchitis, emphysema, healed TB, bronchiectasis, or silicosis. Cough and expectoration are common, but systemic symptoms are infrequent. The course may be slowly progressive, or it may be stable for long periods; persistent hemoptysis and development of respiratory insufficiency are important complications. Radiographic features resemble those of pulmonary TB, but cavitation tends to be thin-walled, and pleural effusion is rare.

In milder cases, observation alone may be sufficient. In moderately advanced symptomatic disease with positive sputum smears and cultures, a three-drug regimen (clarithromycin, rifampin, ethambutol) should be offered. In serious progressive cases unresponsive to standard pharmacologic therapy, combinations of four to six drugs that include rifabutin (experimental), ciprofloxacin (500 to 1000 mg/day), clofazimine (100 to 200 mg/day), and amikacin (10 to 15 mg/kg/day) may be tried. Resectional surgery is recommended in the exceptional case involving well-localized disease in a younger, otherwise healthy patient. M. kansasii and M. xenopi infections are responsive to standard TB regimens, but rifampin and clarithromycin should be included. 

Since the organisms are usually resistant to all single drugs, susceptibility testing is of very limited value. Determination of susceptibility to drug combinations can be helpful but can be obtained only in highly specialized laboratories. 

Lymphadenitis 

In children 1 to 5 yr, chronic submaxillary and submandibular cervical lymphadenitis is commonly due to MAC or M. kansasii. The route of transmission is presumably oral ingestion. Diagnosis is usually made by biopsy. Treatment with clarithromycin, rifampin, and ethambutol should be given to avoid fistulas and disfiguring scars. 

Cutaneous Disease 

Swimming pool granuloma is a protracted but self-limited superficial granulomatous ulcerating disease usually caused by M. marinum contracted from contaminated swimming pools or from cleaning a home aquarium. M. ulcerans and M. kansasii are occasionally involved. Healing may occur spontaneously, but tetracycline (1 to 2 g/day) and combinations of clarithromycin, rifampin, and ethambutol for 3 to 6 mo have shown good results against M. marinum.

Wounds and Foreign Body Infections

M. fortuitum complex has been involved in a number of serious cases of penetrating wounds of the skin (especially feet) and eyes, and of contaminated materials (porcine heart valves, breast implants, bone wax). Treatment is usually extensive debriding and removal of the foreign material. Useful drugs have included clarithromycin, sulfamethoxazole (50 mg/kg/day), doxycycline (200 to 400 mg/day), cefoxitin (200 mg/kg/day), and amikacin (10 to 15 mg/kg/day) with courses of 3 to 6 mo. 

Disseminated disease due to MAC is common in advanced AIDS and occurs occasionally in other immunosuppressed states, including organ transplantation and hairy cell leukemia. In AIDS, the disease is usually a late manifestation occurring comorbidly with other opportunistic infections. This pattern is distinct from TB in AIDS, which is frequently the early presenting or defining infection when CD4 count is > 200/µL. 

Disseminated MAC disease is marked by fever, anemia, thrombocytopenia, diarrhea, and abdominal pain--features similar to Whipple's disease. Diagnosis can be confirmed by cultures of blood, bone marrow, or small-bowel biopsy specimens. Stool and respiratory specimens may also demonstrate the organisms, but these sources may represent colonization rather than true disease. Combinations of antimycobacterial drugs have reduced bacteremia and temporarily lessened symptoms, but no regimen has been truly successful, and the prognosis is poor.

LEPROSY (Hansen's Disease) 

A chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae, which has a unique tropism for peripheral nerves, skin, and mucous membranes. 

Etiology, Epidemiology and Pathogenesis 

M. leprae is an obligate, intracellular parasite that causes leprosy worldwide in > 10 million people. Although most cases occur in Asia, the highest prevalence is in Africa. Endemic foci also exist in Mexico, South and Central America, and the Pacific islands. Almost all of the estimated 5000 cases in the USA involve immigrants from developing countries who have settled in California, Hawaii, and Texas. The severe lepromatous form is more common in men than in women. Leprosy may occur at any age, although peak age of onset is in the 2nd and 3rd decades.

Until recently, humans were the only recognized natural reservoir for M. leprae, but 15% of wild armadillos in Louisiana and Texas have been found now with disease, and subhuman primates occasionally harbor the organism. M. leprae can also be found in soil. It does not grow on artificial media but multiplies when injected into the feet of mice. 

Transmission of M. leprae is uncertain. However, about 50% of patients have a history of intimate contact with an infected person, commonly a household member. Untreated lepromatous patients harbor a large number of M. leprae in their nasal mucosa and its secretions, and the organism is thought to be transmitted by nasal droplets. The milder, tuberculoid form is generally considered noncontagious. However, infected soil and insect vectors (eg, bedbugs, mosquitoes) may play a role in transmission. 

The incubation period ranges from 1 to 2 yr, averages 5 to 7 yr, and can be >= 40 yr. M. leprae grow slowly (doubling time, 2 wk). Before clinical symptoms and signs appear, lepromatous patients harbor an enormous number of organisms, many orders of magnitude greater than that in any other bacterial disease.

Clinical Types 

Most people who have been exposed to M. leprae do not become diseased. However, they often develop serum antibodies and cellular immune responses to M. leprae. In those who develop disease, clinical manifestations and severity vary widely. 

• Tuberculoid leprosy is at one end of the spectrum. Patients have one or a few hypopigmented, hypoesthetic macules with well-defined borders, few or no M. leprae, and circulating lymphocytes that recognize M. leprae. The rash, as in all forms of leprosy, is nonpruritic. Peripheral nerves may be damaged and enlarged, are generally asymmetric, and frequently are contiguous to skin lesions. 

• Lepromatous leprosy is at the other end of the spectrum. These patients have symmetric skin nodules or plaques loaded with M. leprae and often have distal peripheral neuropathy; they lack immunity to M. leprae. They may lose eyelashes and eyebrows. In western Mexico and elsewhere in Latin America, patients may have diffuse dermal infiltration with loss of body hair and other skin appendages but have no visible skin nodules, a condition termed diffuse lepromatosis or lepra bonita. Lepromatous patients may develop erythema nodosum leprosum, and those with diffuse lepromatosis may develop the Lucio's phenomenon, a serious reaction associated with ulcers (especially of the legs) that often become secondarily infected, resulting in bacteremia and death. 

• Borderline leprosy is in the middle of the spectrum. This type is unstable and may become more like lepromatous leprosy or may undergo a reversal reaction, becoming more like the tuberculoid form.

Reactional States 

Reactional states are immunologically mediated events resulting in symptoms and signs of inflammation. 

• Lepra type 1 reactions: Patients with borderline leprosy may develop inflammation within preexisting lesions, new areas of skin inflammation and neuritis (painful, tender ulnar and perineal nerves), and possibly fever. If the reaction occurs before therapy, it is termed a downgrading reaction; if it occurs during therapy, a reversal reaction. Both are believed to be associated with a change in cellular immunity and a shift toward lepromatous or tuberculoid leprosy. In reversal reactions, T helper cell dermal infiltration increases significantly, with an associated rise in local cytokines, especially interferon-?.If not treated early, reversal reactions involving nerves can lead to irreversible motor and sensory loss. The only effective treatment is adding corticosteroids to the antimicrobials being used. Prednisone 40 to 60 mg/day po can be used initially followed by low maintenance doses (often as low as 10 to 15 mg/day) for a few months. Corticosteroids generally should not be started unless neuritis, skin inflammation that may become ulcerated, or cosmetically important areas are involved. Minor skin inflammation should not be treated. 

• Lepra type 2 reactions: About 1/2 of patients with lepromatous leprosy develop erythema nodosum leprosum (ENL) in their first few years of effective antimicrobial therapy. This reaction may occur spontaneously before therapy, precipitating the diagnosis, or it may occur up to 10 yr after therapy, when patients have negative reactions to skin smears. ENL is characterized by erythematous and painful papules or subcutaneous nodules that may pustulate and ulcerate, fever, neuritis, lymphadenitis, orchitis, arthritis (particularly in large joints, usually knees), and glomerulonephritis. Histologically, it appears to be a polymorphonuclear vasculitis or panniculitis and is believed to be due to circulating immune complexes or events associated with increased T helper cell function. Levels of circulating tumor necrosis factor increase. It may result in anemia from RBC destruction or bone marrow suppression and hepatic inflammation with mild abnormalities in liver function tests.

First and second episodes of ENL may be treated, if mild, with aspirin or, if significant, with short courses (1 wk) of prednisone 40 to 60 mg/day, in addition to antimicrobials. For recurrent cases, thalidomide 100 to 400 mg/day po is the drug of choice. However, because of its teratogenicity, thalidomide should not be given to women who may become pregnant. Adverse effects are mild constipation, mild leukopenia, and sedation. 

Complications 

Most complications are due to peripheral nerve involvement resulting from the infection and its resultant inflammatory response or neuritis associated with reactions. Nerve trunks and microscopic dermal nerves may be affected. The ulnar nerve at the elbow is most commonly involved, leading to distal hypoesthesia and clawing of the 4th and 5th digits in severe cases. The perineal, median, zygomatic branch of the facial, and posterior auricular nerves may also be involved. Small nerve fibers that respond to hot and cold, fine touch, and pain are particularly affected, while larger nerve fibers responsible for position and vibration sensation are generally spared. 

Tendon transfers may correct functional disabilities of the extremities and lagophthalmos but should not be performed until 6 mo after initiation of therapy or a significant reaction, particularly in any affected nerve distribution. 

Plantar ulcers with secondary infection are a major cause of morbidity and should be treated with debridement and appropriate antibiotics. The patient should wear a total-contact cast that allows ambulation or should avoid weight bearing. To prevent recurrence, calluses should be filed, and patients should wear custom-molded shoes or extra-depth shoes (that do not rub the feet).

The eyes may be severely affected. In lepromatous patients, organisms invade the anterior chamber; ENL may cause iritis, leading to glaucoma. Corneal insensitivity and involvement of the facial nerve's zygomatic branch (causing lagophthalmos) may lead to corneal trauma, scarring, and blindness. Patients with corneal involvement should routinely use lubricating eyedrops. 

The nasal mucosa and cartilage are affected in lepromatous patients; untreated patients often complain of chronic nasal congestion and, at times, epistaxis. Although uncommon, nasal cartilage perforation and collapse may result if leprosy goes untreated. 

Impotence may occur in lepromatous males from decreased serum testosterone levels and increased follicle-stimulating and luteinizing hormone levels, with hypospermia, aspermia, and infertility. Impotence may be ameliorated by monthly injections of testosterone enanthate 200 mg IM or by liberal application to the scrotum of 5% testosterone cream in a hydrophilic base bid. Amyloidosis and consequent renal failure occasionally occur in lepromatous leprosy associated with severe, recurrent ENL. 

Diagnosis and Laboratory Findings 

Diagnosis is suggested by the clinical picture, notably chronic skin lesions and peripheral neuropathy, and confirmed by biopsy. Biopsy specimens should be taken from the advancing edge of tuberculoid lesions, because normal-appearing skin will have pathologic changes. In lepromatous patients, specimens should be taken from nodules or plaques, although pathologic changes can be found even in normal-appearing skin. Skin biopsies from lepromatous patients contain highly vacuolated macrophages (foam cells), few lymphocytes, and numerous acid-fast bacilli (AFB), often in clumps or globi. These cells persist even after years of therapy, when AFB are no longer present. In contrast, biopsies from patients with the tuberculoid form contain granulomas consisting of lymphocytes, epithelioid cells, and foreign body giant cells that have a predilection for dermal appendages, particularly nerves. Occasionally, patients with the tuberculoid form have only a nonspecific, chronic inflammation consisting of a scattered lymphocytic dermal infiltration. Peripheral nerve damage may also occur in sarcoidosis involving the skin, but actual nerve invasion resulting in axonal degeneration and at times caseous necrosis is pathognomonic for leprosy.

Serum IgM antibodies to an M. leprae phenolic glycolipid antigen are specific for these bacilli. Lepromatous patients almost always have antibodies, but only 2/3 of patients with tuberculous leprosy have them. In endemic areas, infected but nondiseased persons often have such antibodies. Thus, the usefulness of serum antibodies to phenolic glycolipid for diagnosing leprosy is limited. However, they may be useful in monitoring disease activity because antibody levels fall with effective chemotherapy and may rise with relapse. Lepromin (heat-killed M. leprae) is available for skin testing. However, because lepromatous patients have negative reactions and those with the tuberculoid form and some nondiseased persons have positive reactions, lepromin is not useful diagnostically. 

Prophylaxis and Treatment 

Prophylaxis with BCG vaccine or dapsone has been only marginally effective and is not recommended. 

With treatment, the medical sequelae are often minor, but the deformities of leprosy can be socially stigmatizing; patients and their families are often ostracized. Treatment for lepromatous leprosy requires more intensive regimens and a greater duration than that for tuberculoid leprosy. Although antimicrobial therapy is effective, optimal regimens remain uncertain. 

For both forms of leprosy, dapsone (4,4´-diaminodiphenylsulfone [DDS]) 50 to 100 mg/day po (for adults) is the mainstay of therapy. Suggested dosages for children are 25 mg 3 times/wk for ages 2 to 6 yr, 25 mg/day for ages 7 to 12 yr, and 50 mg/day for ages 13 to 18 yr. Adverse effects include hemolysis and frank anemia (generally mild); allergic dermatoses that can be severe; and, rarely, a syndrome including an exfoliative dermatitis, high fever, and mononucleosis-like WBC differential (the sulfone syndrome).

Rifampin is primarily bactericidal for M. leprae. However, it is too expensive for many developing countries if given at the recommended 600 mg/day po. Side effects include hepatotoxicity, flu-like syndromes, and, rarely, thrombocytopenia and renal failure when given intermittently. 

Clofazimine, a phenazine dye that is similar to dapsone in activity against M. leprae, is given at oral dosages of 50 mg/day to 100 mg 3 times/wk. A dose of 300 mg/day is moderately active against lepra type 2 reactions and possibly against lepra type 1 reactions. Adverse effects include GI intolerance and an uneven reddish black skin discoloration. 

Ethionamide: 250 to 500 mg/day po is also effective. However, because it causes GI irritability in many patients and may cause liver dysfunction, especially when given with rifampin, it is not advocated unless liver function can be monitored regularly. 

Recently, three antimicrobials: minocycline (100 mg po daily), clarithromycin (500 mg po daily), and ofloxacin (400 mg po daily), have been found to rapidly kill M. leprae and also effectively reduce dermal infiltration in clinical trials of lepromatous leprosy. Their bactericidal activity for M. leprae is greater than that of dapsone, clofazimine, and ethionamide, but not rifampin. Only minocycline has proven safety for the long-term administration required in leprosy. 

Recommended regimens: Dapsone-resistant leprosy has been reported; most patients with primary dapsone resistance demonstrate only partial resistance and do respond to usual doses. Nevertheless, the WHO recommends multidrug regimens for all forms of leprosy. In the USA, where primary dapsone resistance is rare, drug sensitivity testing in mice is recommended for all newly diagnosed and relapsed multibacillary (lepromatous and borderline) patients. For multibacillary leprosy in adults, the WHO advocates dapsone 100 mg/day, clofazimine 50 mg/day plus 300 mg once monthly, and rifampin 600 mg once monthly. This regimen should be maintained for at least 2 yr or until results of skin biopsies are negative (usually in about 5 yr). For paucibacillary leprosy (tuberculoid leprosy patients without demonstrable AFB), the WHO recommends dapsone 100 mg/day and rifampin 600 mg once monthly for 6 mo. Many authorities in India recommend that treatment be extended to 1 yr. 

In the USA: lepromatous leprosy is treated with dapsone 100 mg/day for life, with an initial 2- to 3-yr regimen of rifampin 600 mg/day. Tuberculoid leprosy is treated only with dapsone 100 mg/day for 5 yr. 

[Source: Merck]